To proposed work aims at further definition of the molecular mechanisms of the polymerization and gelation of deoxyhemoglobin S, exploration of the cellular determinants of red cell sickling and abnormalities of the red cell membrane in sickling disorders, attempts to modify and inhibit gelation, sickling and membrane damage, studies of the functional abnormalities of hemoglobin S- containing red cells, and studies of the intermolecular interactions of mutant hemoglobins between each other and with hemoglobin S. Our approach includes studies of the gelation and polymer solubility of the combinations of hemoglobin S with other mutants and other proteins, measurements of the interrelations between various ligands of hemoglobin on the respiratory functions and sickling properties of red cells containing hemoglobin S, and examination of covalent and noncovalent antisickling agents. We will continue to identify new hemoglobin mutants and investigate their structure-functional relations.